Rethinking Menopause Through the Biology of Personalised Hormone Therapy

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Rethinking Menopause Through the Biology of Personalised Hormone Therapy

07/05/2025 • by The RAM Institute

Gustavo Torres de Souza, PharmD, PhD, explores why women respond differently to hormone replacement therapy and how genetics, metabolism and ageing biology may support more personalised menopause care

Menopause as a systemic transition

Menopause has traditionally been approached primarily as a reproductive milestone characterised by declining ovarian function and the cessation of menstruation. In clinical practice, however, many healthcare professionals recognise that the menopausal transition often extends far beyond vasomotor symptoms alone.1

Changes in body composition, increasing abdominal adiposity, worsening metabolic parameters, sleep disturbances, altered cardiovascular risk profiles, reduced resilience, and progressive changes in overall wellbeing are frequently observed during this period, although with striking variability between women.

Growing evidence suggests that menopause should be understood as a systemic biological transition involving complex interactions between hormonal regulation, adipose tissue biology, metabolism, inflammation, vascular function, and ageing-related processes.

Many women also progressively develop increased visceral adiposity during the menopausal transition, even without major changes in total body weight.

This is clinically relevant because visceral adipose tissue is metabolically active and contributes to insulin resistance, chronic low-grade inflammation, endothelial dysfunction, dyslipidaemia, hypertension, and cardiometabolic disease. As clinicians often observe, some women remain metabolically resilient during menopause, whereas others rapidly develop central obesity, worsening lipid profiles, reduced metabolic flexibility, or accelerated cardiovascular risk. These differences increasingly support the concept that menopause may act as a biological amplifier, revealing or intensifying underlying metabolic, inflammatory, vascular, endocrine, and ageing-related susceptibilities that may previously have remained clinically silent.1

Understanding why women differ so substantially in symptom patterns may require consideration of molecular and physiological variability extending beyond circulating hormone concentrations alone.

Emerging evidence from ageing biology, genomics, metabolism, and systems biology suggests that pathways related to oestrogen signalling, adipose tissue regulation, lipid metabolism, inflammation, coagulation, mitochondrial function, and DNA repair all contribute to this variability. This article therefore discusses menopause as a systemic biological transition and explores how the biology underlying personalised hormone therapy may contribute to more individualised approaches aimed not only at symptom control, but also at healthier ageing, cardiometabolic resilience, functional longevity, and improved long-term quality of life.

Basic genetics for the clinical practice

The foundations of modern genetics date back to the work of Gregor Mendel in the 1860s, when experiments performed in pea plants demonstrated that biological characteristics could be inherited according to reproducible patterns. Although these observations initially appeared relatively simple, they ultimately became the basis for modern molecular genetics.

More than a century later, the Human Genome Project, officially launched in 1990 and completed in 2003, represented one of the largest international scientific collaborations in history. The project successfully mapped and sequenced most of the human genome, identifying approximately 20,000 protein-coding genes and transforming the understanding of human biology and disease. One of its most important consequences was the recognition that many common diseases do not arise from single genetic defects alone, but rather from complex interactions involving numerous genetic variants, environmental factors, metabolism, ageing, and lifestyle.2

More recently, technologies such as CRISPR gene editing have further accelerated interest in translational genetics and precision medicine, illustrating how genetics has evolved from Mendel’s pea plants into a field with direct relevance for modern clinical practice.

At its most fundamental level, human biology follows a relatively simple organisational logic: DNA stores the biological instructions of the cell, RNA acts as an intermediary carrying those instructions, and proteins execute most structural, enzymatic, signalling, and regulatory functions within tissues and organs. Variability within DNA sequences may therefore influence how proteins are produced, regulated, or functionally expressed, contributing to differences in metabolism, inflammation, vascular biology, adipose tissue regulation, hormone signalling, and therapeutic response.

Genes represent specific segments of DNA containing instructions for cellular function. Within these genes, small variations in the genetic code are naturally present between individuals. One of the most common forms of variation is the single nucleotide polymorphism, or SNP, in which a single DNA base differs between individuals. Although individual SNPs may sometimes influence biological pathways, most clinically relevant traits are polygenic rather than monogenic. In other words, obesity, cardiometabolic disease, osteoporosis, menopause-related symptoms, thrombotic susceptibility, and even variability in response to hormone therapy usually emerge from the combined influence of many variants interacting simultaneously with environmental, hormonal, nutritional, behavioural, and ageing-related factors.3

Modern genetics therefore increasingly focuses on pathways and interconnected biological systems rather than isolated genes alone. Variants affecting oestrogen synthesis, receptor signalling, lipid metabolism, inflammation, coagulation, methylation pathways, adipose tissue regulation, or mitochondrial function may each contribute modestly to an overall biological predisposition. Importantly, these variants rarely determine destiny in isolation. Instead, they may influence susceptibility, resilience, metabolic flexibility, tissue response, or probability of developing a given phenotype under specific biological or environmental conditions. 3–5

Within clinical menopause care, this basic genetic logic helps explain how small DNA differences may translate into meaningful biological variability. For example, variants in CYP19A1 may influence aromatase activity and local oestrogen production, while variants in ESR1 may modify how tissues respond to oestrogen signalling. Other variants may affect lipid handling, inflammatory tone, coagulation balance, methylation, or adipose tissue regulation, all of which are relevant during the menopausal transition. These examples do not mean that a single variant determines clinical outcome. Rather, they illustrate how genetics may contribute to differences in hormone availability, tissue sensitivity, metabolic adaptation, vascular risk, and response to HRT.5,6

Menopause, ageing, and cardiometabolic risk

The menopausal transition is increasingly recognised as a cardiometabolic transition, not only an endocrine or reproductive event.1 As discussed in the previous sections, genetics may help explain why women differ in biological predisposition, but the first step is to understand the shared physiological context in which this variability becomes clinically visible.

With the progressive decline in ovarian oestrogen signalling, several systems that are usually discussed separately begin to change together: adipose tissue distribution, insulin sensitivity, lipid metabolism, vascular tone, inflammatory regulation, and endothelial function. Clinically, this is often recognised as a shift in body composition, with greater abdominal or visceral adiposity, sometimes even without a major change in total body weight.

This matters because visceral adipose tissue is not simply a passive energy store. It behaves as an active endocrine and inflammatory organ, producing adipokines, cytokines, and metabolic signals that may contribute to insulin resistance, dyslipidaemia, hypertension, and vascular dysfunction.6

While menopause may not create cardiometabolic vulnerability from nothing, it may reveal or intensify pre-existing susceptibility in women who already have genetic, metabolic, inflammatory, or lifestyle-related risk factors. This interpretation is aligned with major cardiology and menopause literature describing menopause as a period associated with increased central adiposity, adverse lipid changes, metabolic syndrome, vascular remodelling, and higher cardiovascular risk.7

Figure 1. Integrated biological pathways linking menopause, cardiometabolic risk, vascular ageing, and healthy ageing trajectories: Conceptual systems-biology representation illustrating how menopause-associated endocrine changes interact with interconnected metabolic, vascular, inflammatory, coagulation, and ageing-related pathways.

The left column represents the major clinical/system domains associated with the menopausal transition: menopause and hormonal transition (purple), cardiometabolic and vascular health (coral), obesity and metabolic regulation (gold), and healthy ageing and functional longevity (teal).

The central coloured modules represent the principal biological pathways linking these domains. Oestrogen signalling and steroidogenesis (lavender) include CYP19A1, CYP17A1, and ESR1; hormone transport and bioavailability (violet-blue) includes SHBG; DNA repair and ovarian ageing (pink) includes BRCA1, BRCA2, and CHEK2; lipid metabolism and lipoproteins (green-teal) include APOE, CETP, LPA, LPL, ANGPTL3, and ANGPTL4; inflammation and endothelial dysfunction (salmon) includes IL6R; coagulation and thrombotic susceptibility (beige-brown) include F5, F2, PROC, and PROS1; insulin/glucose and adipose regulation (sand) include FTO, MC4R, SH2B1, GCKR, KLF14, and IRS1; and genomic stability and healthy ageing (sage green) include TERT and CDKN2B-AS1.

The coloured connecting arrows indicate shared biological relevance and systems integration across domains rather than direct causal or biochemical reactions. Together, the figure highlights the concept that menopause functions as a systemic biological amplifier, revealing interactions between endocrine ageing, vascular biology, adipose tissue remodelling, metabolic resilience, inflammation, and long-term healthy ageing trajectories.

From a mechanistic point of view, the sequence is best understood as an interconnected network rather than a single linear process. Declining oestrogen signalling may alter adipose tissue biology, reduce favourable effects on vascular function, and contribute to changes in lipid metabolism, including higher LDL cholesterol, triglycerides, and other atherogenic particles in many women.1,7–9 At the same time, expanding visceral adipose tissue may increase chronic low-grade inflammation, which can impair insulin signalling and contribute to endothelial dysfunction.1

The endothelium, the inner cellular lining of blood vessels, is central to vascular health because it regulates vasodilation, vascular tone, coagulation balance, and inflammatory cell recruitment. When endothelial function declines, vascular ageing accelerates and the risk of hypertension, atherosclerosis, and cardiovascular disease may increase. Mitochondrial function and oxidative stress provide another important layer. Oestrogen signalling has been linked to mitochondrial efficiency and antioxidant protection in vascular tissues, and loss of oestrogenic support may favour reactive oxygen species production, impaired cellular energy handling, and redox imbalance.1,10

For clinicians, the practical message is that menopausal cardiometabolic risk is not explained by hormones alone. It reflects the convergence of endocrine ageing, adipose tissue remodelling, inflammageing, mitochondrial stress, lipid dysregulation, and vascular biology. This reinforces the need for individualised treatment for all women.

Why HRT response varies

If we consider two women of similar age entering menopause, both may initially appear clinically comparable: similar symptoms, similar lifestyles, and similar indications for hormone replacement therapy. However, in practice, their responses may differ substantially.11 One woman may experience marked improvement in vasomotor symptoms, sleep, and quality of life with relatively low-dose transdermal oestradiol combined with micronised progesterone, whereas another may require dose adjustments, alternative formulations, or develop breast tenderness, fluid retention, migraine worsening, or limited symptom control despite apparently similar treatment strategies. Increasingly, evidence suggests that these differences are not random, but reflect underlying heterogeneity in vascular biology, adipose tissue distribution, inflammation, coagulation pathways, oestrogen signalling, metabolism, and tissue responsiveness.

Part of this variability becomes clear when we consider how HRT is used in practice. A patient may start with a transdermal oestradiol patch, for example 25 or 50 micrograms, while another may use oestradiol gel, commonly titrated by the number of daily pumps, or an oral oestradiol preparation such as 1 mg or 2 mg tablets.8,11 If the uterus is present, oestrogen must be balanced with endometrial protection, often through micronised progesterone, used cyclically or continuously, or through a levonorgestrel-releasing intrauterine system.

These familiar prescribing differences are not merely logistical. They create different biological exposures. Oral oestrogen passes first through the liver and may increase hepatic production of coagulation-related proteins,12,13 while transdermal oestradiol largely bypasses this first-pass effect and is generally associated with less coagulation activation.12–14 Current guidance therefore emphasises individualisation according to type, dose, route, duration, timing, and whether a progestogen is required.  

In clinical practice, this translates into recognisable decision points. A woman younger than 60 or within 10 years of menopause onset, with severe vasomotor symptoms and low vascular risk, may have a different benefit-risk profile from a woman starting later, or from someone with obesity, high triglycerides, migraine with aura, previous venous thromboembolism, or strong thrombotic family history.15

A woman whose main concern is genitourinary symptoms may require local vaginal oestrogen rather than systemic therapy.14 A patient with a uterus needs adequate progestogen protection, while a woman after hysterectomy generally does not. Lower doses and transdermal routes are often preferred when vascular or thrombotic risk requires caution,11 and symptom response should be reassessed rather than assuming uniform absorption or effect. This is where biology becomes clinically useful: differences in oestrogen transport, receptor signalling, hepatic metabolism, coagulation balance, inflammation, and cardiometabolic resilience help explain why HRT should be individualised rather than treated as a uniform intervention. 

Genetics of hormonal, metabolic, vascular, coagulation, and cancer-related pathways

The biological variability observed during menopause and during hormone replacement therapy reflects the interaction of several pathways rather than a single mechanism.

Examples that illustrate this well include how CYP19A1 and CYP17A1 participate in steroidogenesis and oestrogen synthesis,16 while ESR1 helps explain why the biological effect of oestrogen depends not only on hormone concentration,11 but also on tissue responsiveness to oestrogen signalling. This concept becomes clinically relevant when considering why some women appear more sensitive to hormonal fluctuations, vasomotor symptoms, sleep disruption, changes in body composition, or accelerated bone loss during the menopausal transition.17

SHBG provides another important bridge between endocrine and metabolic biology because circulating SHBG concentrations are closely associated with adiposity, insulin resistance, hepatic metabolism, and cardiometabolic health.6 At the same time, inflammatory pathways involving IL-6 signalling increasingly link menopause with chronic low-grade inflammation,1,5 endothelial dysfunction, and vascular ageing. Lipid-related pathways involving APOE, LPA, and CETP further reinforce that menopausal cardiovascular risk emerges from interactions between endocrine changes, inherited lipid handling, inflammatory tone, and vascular biology.9

As many clinicians recognise in practice, two women with apparently similar menopause timing may evolve very differently with regard to abdominal adiposity, triglyceride accumulation, LDL elevation, endothelial dysfunction, carotid atherosclerosis, or long-term cardiovascular risk. This integrated systems-biology framework is summarised in Figure 2, illustrating how steroidogenesis, hormone transport, inflammation, vascular biology, coagulation, and metabolic pathways interact to influence menopause-related clinical variability and long-term cardiometabolic ageing trajectories.

Figure 2. Steroidogenesis, hormone metabolism, and integrated biological pathways associated with menopause-related cardiometabolic and ageing trajectories. Conceptual systems-biology framework illustrating the interaction between canonical steroidogenesis pathways, menopause-associated endocrine changes, and downstream biological processes relevant to cardiometabolic health, vascular ageing, obesity, inflammation, coagulation balance, and healthy ageing. The left panel summarises major steroidogenic pathways involved in oestrogen, androgen, cortisol, and aldosterone synthesis, including key enzymes such as CYP17A1, CYP19A1, HSD17B, CYP21A2, and CYP11B2.

The central integration layer organises menopause-relevant biological domains according to functional modules, including oestrogen signalling and tissue responsiveness (purple), hormone transport and bioavailability (violet), lipid metabolism and vascular resilience (teal), inflammation and endothelial dysfunction (salmon), coagulation and thrombotic susceptibility (sand), adiposity and insulin resistance (gold), and genomic stability and healthy ageing (green).

Representative genes associated with these pathways include CYP19A1, CYP17A1, ESR1, SHBG, APOE, CETP, LPA, ANGPTL3, ANGPTL4, IL6R, F5, F2, PROC, PROS1, FTO, MC4R, SH2B1, GCKR, KLF14, BRCA1, BRCA2, CHEK2, TERT, and CDKN2B-AS1. The right panel summarises the major clinical domains influenced by these interconnected pathways, including menopause symptoms and HRT variability, cardiometabolic and vascular ageing, obesity and metabolic resilience, and healthy ageing trajectories. Solid arrows represent canonical biochemical reactions, whereas dashed arrows indicate biological and trait-association relationships derived from integrated genomic, metabolic, and ageing-related evidence rather than direct enzymatic conversions.

Coagulation biology provides one of the clearest clinical examples of this variability. Variants such as Factor V Leiden and the prothrombin G20210A mutation help illustrate why thrombotic susceptibility differs substantially between women, particularly in the context of systemic oestrogen exposure.¹⁸

Natural anticoagulant pathways involving PROC and PROS1 further contribute to this biological balance. Importantly, these pathways do not act independently from the broader metabolic and vascular environment. Obesity, endothelial dysfunction, inflammatory activation, smoking, hypertension, migraine with aura, age, and route of hormone administration all interact with coagulation biology to shape individual risk. This is one reason why modern menopause management increasingly emphasises personalised evaluation rather than uniform treatment strategies, particularly when deciding between oral and transdermal oestrogen formulations or when assessing women with previous venous thromboembolism or strong family history of thrombosis.^13,14

Genetics should therefore be interpreted as one additional layer helping clinicians understand interindividual variability in vascular health, metabolic resilience, and long-term ageing trajectories, with the ultimate objective extending beyond symptom control toward healthier ageing, preservation of function, and improved quality of life.

Personalised HRT and preventive strategies

Taken together, these observations increasingly support a more personalised approach to menopause care and hormone replacement therapy. Rather than viewing menopause management exclusively through symptom control, clinicians are progressively integrating broader cardiometabolic, vascular, skeletal, cognitive, and systemic-health considerations into long-term preventive strategies.

In this context, personalised medicine does not imply that treatment decisions are dictated by genetics alone, but rather that molecular and genomic information may function as additional biological layers supporting clinical judgement. Genetic testing may help contextualise interindividual variability in oestrogen signalling, lipid handling, coagulation susceptibility, inflammatory pathways, bone response, hepatic metabolism, or metabolic resilience,^6,17,19 particularly when interpreted together with conventional clinical assessment, family history, symptom burden, body composition, cardiovascular profile, thrombotic risk, and lifestyle factors.²⁰

In practical terms, this may contribute to more individualised therapeutic reasoning regarding oral versus transdermal oestrogen, dose selection, need for closer thrombotic or cardiometabolic monitoring, earlier vascular-risk assessment, lipid and glucose follow-up, bone-health surveillance, nutritional interventions, and preventive strategies targeting obesity and metabolic dysfunction.^11,21,22

Importantly, the value of this approach lies less in predicting a single outcome and more in improving biological understanding of the patient as a whole. As preventive, regenerative, and longevity-oriented medicine continue to evolve, menopause care may increasingly shift toward integrated patient stratification models combining clinical evaluation with molecular and metabolic information in order to support healthier ageing trajectories, preservation of function, metabolic stability, and sustained wellbeing across ageing.

Regenerative and longevity medicine perspective

As menopause medicine evolves, it increasingly overlaps with preventive and longevity-oriented healthcare because many of the biological systems affected during the menopausal transition are directly linked to long-term functional decline and age-related disease.^1,22 As such, menopause care is increasingly associated with preservation of intrinsic capacity, maintenance of bone and muscle health, reduction of central adiposity, support of cardiovascular and cognitive function, optimisation of sleep and metabolic resilience, and promotion of healthier ageing trajectories.^22,23 Importantly, longevity in this setting should not be interpreted merely as lifespan extension, but rather as maintenance of function, autonomy, vitality, and quality of life across later decades.

This broader perspective also aligns menopause care with modern concepts in systems biology and preventive medicine. Throughout the menopausal transition, endocrine ageing continuously interacts with adipose tissue biology, vascular remodelling, inflammation, mitochondrial and metabolic stress, endothelial function, skeletal integrity, and neurocognitive health. These systems do not age independently, and their interaction contributes to the substantial heterogeneity observed between women during midlife and beyond.

From a clinical perspective, this helps explain why menopause management increasingly requires long-term cardiometabolic thinking rather than isolated symptom-based intervention alone. The emerging role of personalised medicine within this field is therefore not to promise speculative “antiageing” therapies, but to support more biologically informed strategies aimed at preserving resilience and reducing the accumulation of age-related dysfunction over time.

In practical terms, this may involve integrating symptom management with vascular-risk assessment, metabolic follow-up, bone-health preservation, nutritional optimisation, physical activity, sleep quality, and, where appropriate, genomic and molecular information.^19,21 Ultimately, the goal of personalised menopause care is not only improvement of symptoms in the present, but support of healthier ageing, functional longevity, cognitive and metabolic stability, and better long-term quality of life.

Conclusion

Menopause is increasingly recognised as a complex biological transition that extends beyond reproductive ageing alone. Changes in hormonal signalling interact with adipose tissue biology, metabolism, vascular function, inflammation and broader ageing-related processes, helping to explain why women may experience markedly different symptom profiles, health trajectories and responses to hormone therapy.

As understanding of these interconnected pathways continues to evolve, menopause care is also becoming more individualised. While genetics, molecular biology and systems medicine are unlikely to replace traditional clinical assessment, they may provide additional insights that help clinicians better understand biological differences between patients and support more personalised treatment strategies.

Importantly, the future of menopause management involves a broader focus on preserving metabolic health, cardiovascular function, skeletal integrity, cognitive wellbeing and overall quality of life throughout ageing. By integrating clinical evaluation with emerging insights from ageing biology and personalised medicine, clinicians may be better positioned to support healthier ageing trajectories and long-term wellbeing for women during midlife and beyond.

Dr Gustavo Torres de Souza is a pharmacist and holds a doctorate in genetics. He has extensive experience in genome editing and the generation of genetically modified animals for heterologous protein production and organ xenotransplantation, developed during his master’s, PhD, and postdoctoral research. Currently Scientific Director at Fagron Genomics, he specialises in pharmacogenetics, leading initiatives to integrate genetic data into clinical practice and optimise therapeutic outcomes. Dr Torres is also a member of the United States Pharmacopeia (USP) Expert Committee on Personalised Therapy and Pharmacogenomics, contributing to global standards and advancing the clinical implementation of personalised medicine.

“This paper provides valuable insights into the role of genetics in ageing processes, particularly within the context of menopause. Menopause represents a complex biological transition characterised by intricate interactions between hormonal regulation, adipose tissue biology, metabolism, inflammation and broader age-related mechanisms.

The article highlights how genetic factors may contribute to the considerable variability observed between individuals during the peri-menopausal and menopausal periods. It also explores how genetic testing can support a more personalised assessment of patients, helping clinicians better understand individual ageing trajectories and biological responses.

Modern genetics is increasingly focused on identifying interconnected pathways and biological systems involved in ageing. This systems-based approach provides valuable insight into the biological complexity of ageing and may help support a more tailored approach to patient evaluation during the critical transition of peri-menopause and menopause.”

Professor Maurizio Cavallini, Scientific Committee member

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